Phosphodiesterase 4 (PDE4) is a validated target for chronic inflammatory diseases such as COPD, asthma, and psoriasis. Although four PDE4 inhibitors have received FDA approval (roflumilast, apremilast, crisaborole, and ensifentrine), all suffer dose-limiting gastrointestinal side effects due to insufficient PDE4B/PDE4D selectivity. Plant-derived natural products offer complementary chemical space for discovering inhibitors with novel binding modes and improved isoform selectivity. This review systematically surveys plant-derived PDE4 inhibitors reported from 1979 to 2024, spanning seven major scaffold classes: flavonoids (∼40%), terpenoids, coumarins, xanthones, benzofurans, fluorenones, and alkaloids. Structure-activity analyses reveal that hydroxylation patterns, C2C3 unsaturation, and B-ring substitution govern flavonoid potency. Structure-guided optimization of toddacoumalone ultimately yielded compound 33a (IC50 = 3.1 nM, PDE4D), the fluorenone selaginpulvilin K (IC50 = 11 nM, 30-909-fold family selectivity), and a semi-synthetic α-mangostin derivative (IC50 = 17 nM). Despite promising potencies, critical gaps persist in subtype selectivity profiling, pharmacokinetic characterization, and metabolic stability. We propose that integrating AI-guided optimization, structure-informed isoform-selective design, nanodelivery systems, and biotechnology-enhanced production can accelerate clinical translation of these scaffolds.